The term “compliance” in the practice of medicine, and specifically in pharmacotherapy, is defined as the “extent to which the patient's behavior coincides with the clinical prescription” (Lift, I. F. and Chuskey, W. R., Compliance with medical regimens during adolescence, Pediatric Clin North Am, 27:3, 1980).
When selecting a medication for a specific patient, many factors are considered, including the medication's efficacy profile, safety profile, route of administration, price, and the compliance of the patient in taking the medication. If a medication must be taken more than once a day, compliance becomes the most important factor in selecting a drug because the pharmacologic efficacy of the medication will be more adversely affected if the medication is not taken as directed. The problem of noncompliance with a prescribed regimen has become so serious that, in response to such a problem, the pharmaceutical industry has developed long-acting forms of many medications.
The problems with noncompliance are particularly pronounced among certain groups of patients. These groups include: (1) pediatric patients, particularly those in child care centers or schools where medications are to be delivered by caregivers or teachers; (2) geriatric patients, whose caregivers are present only intermittently; (3) mentally handicapped individuals, who live independently or whose caregivers are present only intermittently; and (4) disease or disorder specific groups, including patients suffering from alcohol dependence, drug dependence, seizures, certain psychiatric conditions, cardiovascular disease, hypertension, or other conditions.
Accordingly, noncompliance is a problem that is widespread in society. Research has shown that patients only ingest half of the medication that is actually prescribed by physicians (Haynes, R. B., Taylor, D. W., and Sackett, D. L., Compliance in Health Care, Johns Hopkins University Press, Baltimore, 1979). Other studies have shown that up to 93% of medication regimens are not followed as prescribed (Greenberg, R. N., Overview of patient compliance with medication dosing: A literature review, Clin Ther, 6:592–599, 1984). The proportion of those that do not ingest their prescribed medication is greatest when social and cultural barriers, such as a language difficulty, exist, or when a decline in cognitive understanding, such as memory loss, interferes with carrying out instructions. Also, compliance varies with the illness that is treated, the degree of distress associated with symptoms, the complexity of the dosing regimen, the duration of the disease, and the extent of the adverse effects (Del Boca, F. K., Kranzler, H. R., Brown, J., and Korner, P. F., Assessment of medication compliance in alcoholics through UV light detection of a riboflavin tracer, Alcohol Clin Exp Res, 20(8):1412–1417, 1996; Babiker, I. E., Cooke, P. R., and Gillett, M. G., How useful is riboflavin as a tracer of medication compliance?, J. Behav Med, 12:25–38, 1989).
Therefore, noncompliance is a major problem in medicine in general, and in several diseases in particular. As an example, schizophrenia is associated with a noncompliance rate of 11 to 50% with an average of 33% (Maarjberg, K., Aagaard, J., and Vestergard, P., Adherence to lithium prophylaxis: 1. Clinical predictors and patient's reasons for non adherence, Pharmacopsychiatry 21:121–125, 1988; Kane, J. M. and Borenstein, M., Compliance in long-term treatment of schizophrenia, Psychopharmacol Bull, 21:23–27, 1985; Van Putten, T., Why do schizophrenic patients refuse to take their drugs?, Arch Gen Psychiatry, 31:67–72, 1974; Babiker, I. E., Noncompliance in schizophrenia, Psychiat Dev, 4:329–337, 1986). As a result, multiple areas of medicine have been subject to extensive and specific methodologic testing for compliance. For example, the use of riboflavin fluorescence in the urine has been used for testing compliance for various conditions and diseases. These include schizophrenia, clinical drug trials, alcohol dependence, iron deficiency, tricylic antidepressant therapy, hypertension medication, the use of oral contraceptives in adolescents, anti-epileptic drug use, and cardiovascular diseases (Babiker, et al., How useful is riboflavin as a tracer of medication compliance?, J. Behav Med, 12:25–38, 1989; Anton, New methodologies for pharmacological treatment for alcohol dependence, Alcohol Clin Exp Res, 20(7 Suppl):3A–9A, 1996; Cromer, et al., Psychosocial determinants of compliance in adolescents with iron deficiency, Am J. Dis Child, 143(1):55–58, 1989; Gilmore, et al., A study of drug compliance, including the effect of a treatment card, in elderly patients following discharge home from hospital, Aging (Milano), 1(2):153–158, 1989; Perel, Compliance during tricyclic antidepressant therapy: pharmacokinetic and analytical issues, Clin Chem, 34(5):881–887, 1988; Sullivan, et al., Compliance among heavy alcohol users in clinical drug trials, J. Subst Abuse, 1(2):183–194, 1988–1989; Tinguely, et al., Determination of compliance with riboflavin in an antidepressive therapy, Arzneimittelforschung, 35(2):536–538, 1985; Durant, et al., Influence of psychosocial factors on adolescent compliance with oral contraceptives, J. Adolesc Health Care, 5(1):1–6, 1984; Jay, et al., Riboflavin, self-report, serum norethindrone. Comparison of their use as indicators of adolescent compliance with oral contraceptives, Am J. Dis Child, 138(1):70–73, 1984).
Other methods to determine medication regimen compliance include clinical observation of patients, and the analysis of their bodily excretions. One common method of monitoring patients for medication regimen compliance is clinical observation involving individual counseling and close personal supervision by physicians. For example, physicians may observe a patient for physiological signs and symptoms indicative of compliance or noncompliance. These signs and symptoms may include residual signs of illness. Alternatively, the patient may be interviewed regarding the degree of relief from the affliction. A physician might also evaluate physiological changes in the patient. Clinical observation, however, is time consuming and, therefore, expensive. Furthermore, it is dependent on the physician's subjective opinion, and therefore is subject to potential errors.
Still other methods of obtaining compliance information include qualitative urine monitoring methods. One example is the standard laboratory procedure known as enzyme-multiplied immunoassay (EMIT). Utilizing an arbitrary cutoff value, these methods provide the clinician with a simple positive or negative indication of the possible presence or absence of a parent drug or its metabolites in a patient's urine. Urine monitoring methods may also be used to provide a quantitative analysis of ingestion of medication. However, whether qualitative or quantitative, several drawbacks exist in these analytical methods.
First, these analytical methods and tests are time and laborintensive, often requiring the use of complex equipment in the analysis, and thus are not particularly useful when the time period between medication dosages is short. Second, these methods generally require a trained technician to perform the analysis. Third, the analysis is often performed at a location remote to the site where the sample is obtained. Finally, the sample collection itself, for example, obtaining a urine sample, involves a heightened degree of intrusiveness for the patient. As a result, these methods are not amenable to a rapid, generally non-intrusive, on-site assessment of compliance.
In an attempt to ameliorate some of the above-discussed problems of the monitoring methods of the prior art, markers have been used to determine the presence of medication in the system of a subject. However, these methods still require that the urine or stool of a subject be examined by a trained professional to detect the presence of the marker. Thus, while reducing some of the time and complexity involved, these tests are still not useful as a “home” test, still require some heightened degree of time, labor and expense, and do nothing to reduce the intrusiveness experienced by the patient.
While providing useful information relative to patient status and treatment compliance, the clinical monitoring methods described above have distinct drawbacks which limit their usefulness in determining compliance. Thus, it would be desirable to have a monitoring method that is rapid, simple, and inexpensive. Furthermore, it would be desirable for such a test to be amenable to use in the home by laypersons. Still further, it would be desirable for such a test to be minimally intrusive to the patient.